Optically active 1,4-dihydropyridine derivatives and process for the preparation thereof

ABSTRACT

Optically active 1,4-dihydropyridine derivatives represented by general formula (I) and anion salts thereof and a production method therefor: ##STR1## (wherein R 1  represents a C 1-6  alkyl group, R 2  represents a nitrogen-containing heterocyclic group forming a quaternary ammonium which may be substituted, and n is an integer of 1, 2 or 3). The optically active 1,4-dihydropyridine derivatives represented by general formula (I) have vasodilating activity and hypotensive activity and are excellent in water solubility so that they are useful as a drug for circulatory system such as a hypotensor or vasodilator.

TECHNICAL FIELD

The present invention relates to optically active 1,4-dihydropyridinederivatives useful as circulatory system drugs such as hypotensors andvasodilators and to a production method therefor.

BACKGROUND ART

1,4-Dihydropyridine derivatives, such as nifedipine and nirvadipine,have calcium antagonism and, hence, are useful as a circulatory systemdrug such as a hypotensor and a vasodilator. However, their watersolubility is insufficient so that it has been tried to convert theminto inclusion compounds with cyclodextrin, i.e., forms with anincreased water solubility, in order to impart them with pharmaceuticalcharacteristics such as bioavailability and controlled release (JapanesePatent Application (Kokai) No. 6-100537).

It has also been tried to increase the water solubility of1,4-dihydropyridine derivatives by introducing a basic tertiary aminogroup into themselves to form a medically acceptable salt.

For example,(4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid (3S)-3-(1-benzyl-3-pyrrolidinyl) ester 5-methyl ester (YM-09730)represented by the following formula ##STR2## [J. Med. Chem., 29, 2504(1986)],(4S)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-diydropyridine-3,5-dicarboxylicacid 3-{2-[4-(4-benzhydryl-1-piperazinyl)phenyl]ethyl} ester 5-methylester represented by the following formula ##STR3## [Chem. Pharm. Bull.,39, 108 (1991)] and salts thereof are known to have calcium antagonisticactivity as well as vasodilating activity and hypotensive activity, withthese activities lasting [Arzneim. -Forsch./Drug Res. 38(11),1666(1988), J. Med. Chem., 29, 2504 (1986), and Japanese PatentPublication (Kokoku) No. 57-30111]

However, only few 1,4-dihydropyridine derivatives have been known thatthemselves have electric charges and are imparted with, in a sense,permanent water solubility [J. Med. Chem., 3, 3743 (1993)].

Therefore, an object of the present invention is to provide opticallyactive 1,4-dihydropyridine derivatives having themselves electriccharges and permanently having water solubility.

Another object of the present invention is to provide a productionmethod for producing such optically active 1,4-dihydropyridinederivatives.

DISCLOSURE OF THE INVENTION

As a result of intensive investigation, the present inventors have foundthat novel optically active 1,4-dihydropyridine derivatives representedby general formula (I) ##STR4## (wherein R¹ represents a C₁₋₆ alkylgroup, R² represents a nitrogen-containing heterocyclic group forming aquaternary ammonium salt which may be substituted, and n is an integerof 1, 2 or 3) and anion salts thereof have excellent vasodilating andhypotensive activities and also excellent water solubility, andcompleted the present invention based on the discovery.

That is, the present invention relates to optically active1,4-dihydropyridine derivatives represented by general formula (I)##STR5## (wherein the symbols have the same meanings as defined above)and anion salts thereof and to a production method therefor.

Hereafter, the present invention will be described in greater detail.

In general formula (I), the C₁₋₆ alkyl group represented by R¹ may be alinear, branched or cyclic alkyl group. Its examples include a methylgroup, an ethyl group, a propyl group, an isopropyl group, a butylgroup, a t-butyl group, and a cyclohexyl group.

In general formula (I), the nitrogen-containing heterocyclic grouprepresented by R² may include at least one nitrogen atom as aring-forming atom and form a quaternary ammonium. The heterocyclic ringis preferably an aromatic ring, examples of which include a pyridiniumgroup, a pyridazinium group, a pyrimidinium group, a pyrazinium group, atriazinium group, an imidazolium group, a pyrazolium group, an oxazoliumgroup, and a thiazolium group.

These heterocyclic groups may be substituted. Examples of thesubstituent include a cyano group, a C₁₋₄ alkyl group, a C₂₋₅alkoxycarbonyl group, a dialkylamino group having 1-4 carbon atoms ineach alkyl moiety, and a carbamoyl group. Preferred examples of R²include pyridinium, 4-methylpyridinium, 3-carbamoylpyridinium,3-cyanopyridinium, 3-methoxycarbonylpyridinium,4-dimethylaminopyridinium, N-methylpyridinium-2-yl, pyridazinium,3-methylpyridazinium, 3-cyanopyridazinium, pyrimidinium,2-methylpyrimidinium, 4-cyanopyrimidinium, 4-carbamoylpyrimidinium,pyrazinium, 2-methylpyrazinium, 2-carbamoylpyrazinium,2-cyanopyrazinium, triazinium, N-methylimidazolium, N-ethylimidazolium,N-methylpyrazolium, oxazolium, and thiazolium.

[Production Method]

(A) Of the optically active 1,4-dihydropyridine derivatives of thepresent invention represented by general formula (I) above, thosecompounds of which the ring-forming nitrogen atom in R² is connected toa methylene group to form a quaternary ammonium and which arerepresented by general formula (Ia) ##STR6## has the same meaning as R²above, provided that the ring-forming nitrogen atom is connected to amethylene group to form a quaternary ammonium, and R¹ and n have thesame meanings as defined above) can be produced by condensing anoptically active 1,4-dihydropyridine derivative represented by generalformula (II) with an alkyl dihalide represented by general formula (III)to obtain an optically active 1,4-dihydropyridine derivative representedby general formula (IV) and reacting this derivative with anitrogen-containing heterocyclic compound represented by general formula(V) to convert it to a quaternary ammonium as shown in Reaction Scheme Abelow. ##STR7##

In Reaction Scheme A above, X represents a halogen atom and othersymbols have the same meanings as defined above.

The condensation reaction between the compound represented by generalformula (II) and the compound represented by general formula (III) canbe carried out by a known method. For example, this reaction can beperformed by dissolving the compound represented by general formula (II)in a solvent which is inert in itself (for example, tetrahydrofuran,N,N-dimethylformamide, dioxane, chloroform, toluene, or the like) andreacting it with the alkyl dihalide represented by general formula (III)in the presence of an inorganic base (for example, sodium carbonate,potassium carbonate, sodium hydride, or the like) or an organic base(for example, triethylamine, pyridine, lutidine, N-methylmorpholine, orthe like).

Here, the optically active intermediates represented by general formula(II) are known and can be produced by the chemical method of Sibanuma etal. [Chem. Pharm. Bull., Vol.28, 2809 (1980)], enzymatic method ofAchiwa et al. [Tetrahedron Letters, 32, 5805 (1991)], and enzymaticmethod of Charles J. Sih et al. [Tetrahedron Letters, 32, 3465 (1991)].

Also, the halogen atom represented by X in general formula (III)includes chlorine, bromine, iodine, etc. Specific examples of thecompound represented by general formula (III) include1,2-dichloroethane, 1,2-dibromoethane, 1,2-diiodoethane,1,3-dichloropropane, 1,3-dibromopropane, 1,3-diiodopropane, etc.

The reaction between the resulting optically active form represented bygeneral formula (IV) and the nitrogen-containing heterocyclic compoundrepresented by general formula (V) can also be performed by a knownmethod.

That is, the reaction is carried out by heating the two compounds at 50to 150° C., preferably 80 to 120° C., after dissolving them in a solventwhich is inert in itself, for example, toluene, isopropyl ether,acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, or thelike, or without using any solvent.

Here, the nitrogen-containing heterocyclic compound represented bygeneral formula (V) is a heterocyclic compound having at least onenitrogen atom as a ring-forming atom, preferably an aromatic compound.Specific examples thereof include pyridine, pyridazine, pyrimidine,pyrazine, triazine, imidazole, pyrazole, oxazole, thiazole, etc. Theseheterocyclic compounds may be substituted. The substituents include acyano group, a C₁₋₄ alkyl group, a C₂₋₅ alkoxycarbonyl group, adialkylamino group having 1 to 4 carbon atoms in each alkyl moiety, acarbamoyl group, etc. Preferred heterocyclic compounds are pyridine,4-methylpyridine, 3-carbamoylpyridine, 3-cyanopyridine,3-methoxycarbonylpyridine, 4-dimethylaminopyridine, pyridazine,3-methylpyridazine, 3-cyanopyridazine, pyrimidine, 2-methylpyrimidine,4-cyanopyrimidine, 4-carbamoylpyrimidine, pyrazine, 2-methylpyrazine,2-carbamoylpyrazine, 2-cyanopyrazine, triazine, N-methylimidazole,N-ethylimidazole, N-methylpyrazole, oxazole, thiazole, etc.

(B) Of the optically active 1,4-dihydropyridine derivatives representedby general formula (I) above, those compounds of which R² is connectedto the methylene group through an atom other than the nitrogen atom thatforms a quaternary ammonium and which is represented by general formula(Ib) ##STR8## has the same meaning as R² above, [provided that thering-forming atoms include a nitrogen atom which is not connected to themethylene group], R³ represents a C₁₋₆ alkyl group, and R¹ and n havethe same meanings as defined above) can be produced by reacting theoptically active 1,4-dihydropyridine derivative represented by generalformula (II) with the compound represented by general formula (VI) toobtain an optically active 1,4-dihydropyridine derivative represented bygeneral formula (VII) and alkylating this derivative to convert it to aquaternary ammonium as shown in Reaction Scheme B below. ##STR9##represents a nitrogen-containing heterocyclic group which may besubstituted, provided that the ring-forming atoms include a nitrogenatom which is not connected to the methylene group, Y represents ahydroxyl group or a halogen atom, and other symbols have the samemeanings as defined above.

The reaction between the compound represented by general formula (II)and the compound represented by general formula (VI) can be carried outby a known method.

For example, the reaction is performed by dissolving the compoundrepresented by general formula (II) in a solvent which is inert initself (for example, toluene, isopropyl ether, acetonitrile,tetrahydrofuran, N,N-dimethylformamide, dioxane, etc.) in the presenceof an inorganic base (for example, sodium hydrogen carbonate, potassiumhydrogen carbonate, sodium carbonate, potassium carbonate, etc.) and/oran organic base (for example, triethylamine, pyridine, lutidine,N-methylmorpholine, etc.) or in the presence of a suitable condensingagent, for example, dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, and reacting it with thecompound represented by general formula (VI).

Here, in general formula (VI), the heterocyclic group represented by##STR10## is a heterocyclic group which has at least one nitrogen atomas a nitrogen-forming atom, preferably an aromatic ring. Specificexamples include pyridyl, pyridazyl, pyrimidyl, pyrazyl, triazyl,imdazolyl, pyrazolyl, oxazolyl, thiazolyl, etc. These heterocyclicgroups may be substituted. The substituents include a cyano group, aC₁₋₄ alkyl group, a C₂₋₅ alkoxycarbonyl group, a dialkylamino grouphaving 1 to 4 carbon atoms in each alkyl moiety, a carbamoyl group, etc.The halogen atom represented by Y includes chlorine, bromine, iodine,etc.

Specific examples of the compound represented by general formula (VI)include 2-(chloromethyl)pyridine, 2-(bromomethyl)pyridine,3-(chloromethyl)pyridine, 4-(bromomethyl)pyridine,2-(hydroxymethyl)pyridine, 3-(hydroxymethyl)pyridine,2-(2-chloroethyl)pyridine, 2-(2-bromoethyl)pyridine,3-(2-chloroethyl)pyridine, 4-(2-bromoethyl)pyridine,2-(2-hydroxyethyl)pyridine, 3-(2-hydroxyethyl)pyridine, etc.

The alkylation of the resulting optically active form represented bygeneral formula (VII) can be carried out by heating the optically activeform and a C₁₋₆ alkyl halide, for example, methyl iodide, ethyl iodide,or bromoethane at 50 to 150° C., preferably 60 to 120° C., afterdissolving them in a solvent which is inert in itself, for example,toluene, isopropyl ether, acetonitrile, tetrahydrofuran,N,N-dimethylformamide, dioxane, or the like, or without using anysolvent.

[Anion salt]

The optically active 1,4-dihydropyridine derivatives of the presentinvention are obtained in the form of anion salts which are derived fromraw materials (halogen compounds) used in the production method. Thatis, the 1,4-dihydropyridine derivatives represented by general formula(Ia) can be obtained as anion salts of the halogen atom X in the alkyldihalide in general formula (III). Also, the 1,4-dihydropyridinederivatives represented by general formula (Ib) can be obtained as anionsalts of the halogen atom in the alkylating agent used in the finalstep.

In the present invention, the anion salts represented by generalformulae (Ia) or (Ib) can be converted to anion salts other than thoseanion salts which are derived from the above-described raw materials bya conventional method.

Preferred anion salts are hydroxyl ions (OH⁻), phosphate ions (PO₄ ³⁻),sulfate ions (SO₄ ²⁻), carbonate ions (CO₃ ²⁻), nitrate ions (NO₃ ⁻),bromide ions (Br⁻), chloride ions (Cl⁻), and fluoride ions (F⁻).

BEST MODE FOR CARRYING OUT THE INVENTION

Hereafter, the present invention will be described by examples,reference examples and test examples. However, the present inventionshould not be construed as being limited thereto.

EXAMPLE 1

Production of 3-Iodopropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylate##STR11##

To a solution of 6 g (8.07 mmol) of(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid in 20 ml of N,N-dimethylformamide (DMF) were added 2.75 g (9.88mmol) of potassium carbonate and 4.2 ml (36.14 mmol) of1,3-diiodopropane, and the mixture was stirred at room temperature for 4hours. The reaction mixture was diluted with 500 ml of ethyl acetate andwashed with water (300 ml×2). The ethyl acetate layer was dehydrated anddried over salt cake and the solvent was distilled off under reducedpressure. The residue was passed through silica gel column(toluene-ethyl acetate) for purification to obtain 5.93 g of the targetcompound.

¹ H-NMR (CDCl₃): δ 8.10 (1H, t, J=2.2), 8.02 (1H, ddd, J=7.7 Hz, 2.2 Hz,1.1 Hz), 7.63 (1H, d, J=7.7 Hz), 7.41 (1H, t, J=7.7 Hz), 5.84 (1H, s),5.08 (1H, s), 4.14-4.20 (1H, m), 4.05-4.11 (1H, m), 3.66 (3H, s),2.98-3.08 (2H, m), 2.39 (3H, s), 2.36 (3H, s), 2.05-2.12 (2H, m),

FAB-MS(m/z): 501(M+1)

EXAMPLE 2

Production of 3-pyridiniumpropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR12##

To 657 mg (1.31 mmol) of the 3-iodopropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateobtained in Example 1 was added 1.1 ml (13.14 mmol) of pyridine and themixture was stirred at 80° C. for 4 hours. To the reaction mixture wasadded 5 ml of chloroform and the resulting mixture was stirred at roomtemperature for 30 minutes and the crystals formed were filtered toobtain 563 mg of the target compound.

¹ H-NMR (CD₃ OD): δ 8.96 (2H, d, J=5.5 HZ), 8.60 (1H, t, J=8.1 Hz),7.99-8.13 (3H, m), 8.00 (1H, ddd, J=8.1 Hz, 2.2 Hz, 1.1 Hz), 7.63-7.65(1H, m), 7.48 (1H, t, J=8.1 Hz), 4.97 (1H, s), 4.62-4.70 (2H, m),4.10-4.24 (2H, m), 3.65 (3H, s), 2.35-2.42 (2H, m), 2.34 (3H, s), 2.33(3H, s),

FAB-MS(m/z): 452(M⁺)

EXAMPLE 3

Production of 3-pyraziniumpropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR13##

To a solution of 1.46 g (2.92 mmol) of the 3-iodopropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateobtained in Example 1 in 2.5 ml of tetrahydrofuran (THF) was added 1.17g (14.58 mmol) of pyrazine and the mixture was stirred at 100° C. for 3hours. To the reaction mixture was added 5 ml of ethyl acetate and themixture was stirred at room temperature for 30 minutes. The crystalsformed were filtered to obtain 1.17 g of the target compound.

¹ H-NMR (CD₃ OD): δ 9.48 (2H, s), 9.10 (2H, s), 8.08 (1H, s), 8.01 (1H,ddd, J=8.1 Hz, 2.2 Hz, 1.1 Hz), 7.65 (1H, d, J=8.1 Hz), 7.48 (1H, t,J=8.1 Hz), 4.99 (1H, s), 4.71-4.77 (2H, m), 4.15-4.28 (2H, m), 3.65 (3H,s), 2.42-2.45 (2H, m), 2.35 (3H, s), 2.33 (3H, s),

FAB-MS(m/z): 453(M⁺)

EXAMPLE 4

Production of 3-thiazoliumpropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR14##

To a solution of 1.00 g (2.00 mmol) of the 3-iodopropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateobtained in Example 1 in 2.5 ml of THF was added 710 μl (10.00 mmol) ofthiazole and the mixture was stirred at 80° C. for 3 hours. The crystalsformed were filtered to obtain 515 mg of the target compound.

¹ H-NMR (CD₃ OD): δ 8.46 (1H, d, J=3.7), 8.28 (1H, d, J=4.0), 8.08 (1H,s), 8.00 (1H, dd, J=8.1 Hz, 2.2 Hz), 7.65 (1H, d, J=7.7 Hz), 7.48 (1H,t, J=7.7 Hz), 5.01(1H, s), 4.58-4.63 (2H, m), 4.11-4.20 (2H, m), 3.64(3H, s), 2.33-2.38 (2H, m), 2.34 (3H, s), 2.33 (3H, s),

FAB-MS(m/z): 458(M⁺)

EXAMPLE 5

Production of 3-pyridaziniumpropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR15##

To a solution of 1.00 g (2.00 mmol) of the 3-iodopropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateobtained in Example 1 in 2 ml of THF was added 720 μl (10.00 mmol) ofpyridazine and the mixture was stirred at 80° C. for 3 hours. A smallamount of toluene was added to the reaction mixture, which wassubsequently stirred. The crystals formed were filtered. 10 ml of THFwas added to the crystals and the mixture was stirred at roomtemperature for 30 minutes and then filtered to obtain 881 mg of thetarget compound.

¹ H-NMR (CD₃ OD) : δ 9.82 (1H, d, J=5.9 Hz), 9.52 (1H, s), 8.62-8.66(1H,8.53-8.56 (1H, m), 8.09 (1H, s), 8.01 (1H, ddd, J=7.7 Hz, 2.2 Hz, 1.1Hz), 8.65 (1H, dd, J=7.7 Hz, 1.1 Hz), 7.48 (1H, t, J=7.7 Hz), 4.99 (1H,s), 4.81-4.84 (2H, m), 4.19-4.22 (2H, m), 3.65 (3H, s), 2.43-2.48 (2H,m), 2.36(3H, s), 2.35 (3H, s),

FAB-MS(m/z): 453(M⁺)

EXAMPLE 6

Production of 3-(1-methylimidazolium)propyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR16##

To a solution of 1.00 g (2.00 mmol) of the 3-iodopropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateobtained in Example 1 in 2.5 ml of THF was added 820 mg (10.00 mmol) of1-methylimidazole and the mixture was stirred at 80° C. for 2 hours. Tothe reaction mixture were added 10 ml of ethyl acetate and 10 ml oftoluene, and the mixture was stirred at room temperature for 2 hours.The deposit was passed through silica gel column for purification toobtain 231 mg of the target compound.

¹ H-NMR (CD₃ OD): δ 8.08 (1H, s), 8.00 (1H, d, J=8.1 Hz), 7.65 (1H, d,J=8.1 Hz), 7.57-7.58 (2H, m), 7.48 (1H, t, J=8.1 Hz), 5.03 (1H, s),4.18-4.22 (2H, m), 4.10-4.14 (2H, m), 3.92 (3H, s), 3.64 (3H, s), 2.36(3H, s), 2.33 (3H, s), 2.18-2.25 (2H, m),

FAB-MS(m/z): 455(M⁺)

EXAMPLE 7

Production of 3-(3-methoxycarbonylpyridinium)propyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR17##

To a solution of 1.00 g (2.00 mmol) of the 3-iodopropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateobtained in Example 1 in 2 ml of THF was added 1.37 g (10.00 mmol) ofmethyl nicotinate and the mixture was stirred at 80° C. for 3.5 hours.The crystals which deposited were filtered to obtain 489 mg of thetarget compound.

¹ H-NMR (CD₃ OD): δ 9.53 (1H, s), 9.20 (1H, d, J=6.2 Hz), 9.03 (1H, dt,J=8.1 Hz, 1.5 Hz), 8.25 (1H, t, J=6.6 Hz), 8.03 (1H, t, J=2.2 Hz), 7.99(1H, dd, J=7.7 Hz, 1.1 Hz), 7.61 (1H, d, J=7.7 Hz), 7.47(1H,d,J=7.7 Hz),4.82(1H,s), 4.71-4.80(2H, m), 4.26-4.32 (1H, m), 4.12-4.18 (1H, m), 4.06(3H, s), 3.65 (3H, s), 2.40-2.47 (2H, m), 2.33 (3H, s), 2.32 (3H, s),

FAB-MS(m/z): 510 (M⁺)

EXAMPLE 8

Production of 3-(3-cyanopyridinium)propyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR18##

To a solution of 1.00 g (2.00 mmol) of the 3-iodopropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateobtained in Example 1 in 2 ml of THF was added 920 mg (10.00 mmol) ofnicotinonitrile and the mixture was stirred at 80° C. for 4.25 hours.The crystals which deposited were filtered to obtain 183 mg of thetarget compound.

¹ H-NMR (CD₃ OD) : δ 9.66 (1H, s), 9.27 (1H, d, J=6.6 Hz), 8.98 (1H, dt,J=8.1 Hz, 1.1 Hz), 8.31 (1H, dd, J=8.1 Hz, 6.6 Hz), 8.05 (1H, t, J=2.2Hz), 8.00 (1H, ddd, J=8.1 Hz, 2.2 Hz, 1.1 Hz), 7.63 (1H, dd, J=7.7 Hz,1.1 Hz), 7.46 (1H, t, J=8.1 Hz), 4.92 (1H, s), 4.68-4.79 (2H, m),4.24-4.30 (1H, m), 4.13-4.19 (1H, m), 3.65 (3H, s), 2.40-2.48 (2H, m),2.35 (3H, s), 2.34 (3H, s),

FAB-MS(m/z): 477 (M⁺)

EXAMPLE 9

Production of 3-(4-dimethylaminopyridinium)propyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR19##

To a solution of 1.00 g (2.00 mmol) of the 3-iodopropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateobtained in Example 1 in 4 ml of THF was added 1.22 g (10.00 mmol) of4-dimethylaminopyridine and the mixture was stirred at 100° C. for 2hours. The crystals which deposited were filtered to obtain 1.09 g ofthe target compound.

¹ H-NMR (CD₃ OD):δ 8.07 (3H, d, J=8.1 Hz), 8.00 (1H, d, J=8.1 Hz), 7.64(1H, d, J=7.7 Hz), 7.48 (1H, t, J=8.1 Hz), 6.96 (2H, d, J=7.7 Hz), 4.95(1H, s), 4.12-4.25 (3H, m), 4.03-4.08 (1H, m), 3.64 (3H, s), 3.23 (6H,s), 2.34 (3H, s), 2.33 (3H, s), 2.18-2.24 (2H, m),

FAB-MS(m/z): 495 (M⁺)

EXAMPLE 10

Production of 3-(3-carbamoylpyridinium)propyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR20##

To a solution of 1.00 g (2.00 mmol) of the 3-iodopropyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateobtained in Example 1 in 4 ml of THF was added 1.22 g (10.00 mmol) ofnicotinamide and the mixture was stirred at 80° C. for 3 hours. Thecrystals which deposited were filtered. To the crystal thus obtained wasadded 10 ml of THF and the mixture was stirred at room temperature for30 minutes and filtered to obtain 292 mg of the target compound.

¹ H-NMR (CD₃ OD) : δ 9.41 (1H, s), 9.11 (1H, d, J=6.2 Hz), 7.22 (1H, dd,J=8.1 Hz, 6.2 Hz), 8.05 (1H, t, J=1.8 Hz), 7.99 (1H, dt, J=8.1 Hz, 1.1Hz), 7.63 (1H, d, J=7.7 Hz), 7.47 (1H, t, J=8.1 Hz), 4.90(1H,s),4.67-4.80(2H,m), 4.24-4.30(1H,m), 4.13-4.17(1H,m), 3.65(3H,s),2.42-2.47(2H,m), 2.33(6H, s),

FAB-MS(m/z): 495 (M⁺)

EXAMPLE 11

Production of 3-(1-methyl-2-pyridinium)methyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR21##

To a solution of 1 g (3.01 mmol) of(4R)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylicacid in 4 ml of THF were added 1.23 g (7.50 mmol) of2-(chloromethyl)pyridine and 460 mg (3.35 mmol) of potassium carbonateand the mixture was stirred at room temperature for 5 hours. The mixturewas diluted with 50 ml of ethyl acetate, washed with water, and hydratedand dried over salt cake. Thereafter, the solvent was distilled offunder reduced pressure to obtain 1.13 g of the residue. The residue waspassed through a silica gel column for purification to obtain 673 mg of3-(2-pyridyl)methyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylate.To a solution of 673 mg of the compound thus obtained in 1 ml of THF wasadded 1 ml of methyl iodide and the mixture was stirred at 60° C. for 2hours. The crystals which deposited were filtered to obtain 526 mg ofthe target compound.

¹ H-NMR (CD₃ OD): δ 8.89 (1H, d, J=6.2 Hz), 8.46 (1H, t, J=7.7 Hz),7.96-8.04 (3H, m), 7.80 (1H, d, J=8.1 Hz), 7.67 (1H, d, J=8.1 Hz), 7.63(1H, d, J=7.7 Hz), 7.48 (1H, t, J=7.7 Hz), 5.13 (1H, s), 4.80-4.84 (2H,m), 4.25 (3H, s), 4.13-4.17 (1H, m), 3.63 (3H, s), 2.40 (3H, s), 2.33(6H, s),

FAB-MS(m/z): 438 (M⁺)

EXAMPLE 12

Production of 3-(1-methyl-3-pyridinium)propyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylateiodide ##STR22##

To a solution of 500 mg (1.51 mmol) of(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylicacid in 3 ml of THF were added 300 ml (2.25 mmol) of 3-pyridinepropanoland 475 mg (3.00 mmol) of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide and the mixture was stirred at 80° C. for 4 hours. Afterconcentration, the reaction mixture was diluted with 50 ml of ethylacetate, washed with water, and hydrated and dried over salt cake.Thereafter, the solvent was distilled off under reduced pressure toobtain 680 mg of the residue. The residue was passed through a silicagel column for purification to obtain 241 mg of 3-(3-pyridyl)propyl(4S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylate.To a solution of 241 mg of the compound thus obtained in 1 ml of THF wasadded 330 μl of methyl iodide and the mixture was stirred at 60° C. for1 hour. The crystals which deposited were filtered to obtain 229 mg ofthe target compound.

¹ H-NMR (CD₃ OD): δ 8.89 (1H, d, J=6.2 Hz), 7.96-8.44 (3H, m), 7.80 (1H,d, J=8.1 Hz), 6.67 (1H, d, J=8.1 Hz), 7.48 (1H, t, J=7.7 Hz), 5.13 (1H,s), 4.83 (2H, s), 4.25 (3H, s), 3.63 (3H, s), 2.40 (3H, s), 2.32 (3H,s),

FAB-MS(m/z): 438 (M⁺)

TEST EXAMPLE 1

Test for solubility in water

The solubility in water of the compounds obtained in Examples 2 to 12were measured. The measurements were performed by mixing deionized waterwith a compound to be tested, subsequently stirring for 3 minutes usinga electromagnetic vibrating stirrer, and determining a critical value(solubility) based on presence or absence of insoluble matter.

As a control compound, the solubility of nifedipine was measured in thesame manner.

As a result, the solubility of nifedipine was 0.1 mg/ml or less whereasthe compounds of Examples 2 to 12 showed respective solubilities of notlower than 1.0 mg/ml.

TEST EXAMPLE 2

The pharmacological activity of the optically active 1,4-dihydropyridinederivatives of the present invention was confirmed by experiments ofdilation against high potassium contraction of rat thoracic aorta.

Thoracic aorta was extracted from a Wistar rat (male, aged 9-12 weeks)and after removing the connective tissue, adipose tissue and the like,there was prepared a spiral specimen of 2 mm wide and 15 mm long. Theblood vessel specimen thus obtained was suspended at 37° C. under a loadof 1 g in an extracted organ incubator containing 10 ml of a nutrientsolution (NaCl: 137 mM, KCl: 5.4 mM, CaCl₂ : 1.5 mM, MgCl₂ : 1 mM,NaHCO₃ : 23.8 mM, glucose: 5.5 mM, pH 7.4) aerated with a mixed gasconsisting of 95% oxygen and 5% carbon dioxide, and equilibrated forabout 1 hour. The nutrient solution in the extracted organ incubator wasexchanged with high concentration potassium ion nutrient solution (NaCl:77 mM, KCl: 65.4 mM, CaCl₂ : 1.5 mM, MgCl₂ : 1 mM, NaHCO₃ : 23.8 mM,glucose: 5.5 mM, pH 7.4) to cause contraction of the blood vesselspecimen. After the contraction reached a stationary stage, testsubstances (the compounds of Examples 3, 4, 6, 7, 8, and 10 andnifedipine) were added in the incubator and their contraction inhibitingeffects were evaluated.

The results obtained are shown in Table below.

                  TABLE 1                                                         ______________________________________                                          #STR23##                                                                      compound  R                     IC.sub.50 (p mol/l)                         ______________________________________                                          Example 3                                                                                                   2.2 24##                                         - Example 4                                                                                                3.7 25##                                         - Example 6                                                                                                1.8 26##                                         - Example 7                                                                                                3.3 27##                                         - Example 8                                                                                                2.0 28##                                         - Example 10                                                                                               2.7 29##                                         - Control --CH.sub.3 3                                                        (nifedipine)                                                               ______________________________________                                    

From the table, it can be seen that the optically active1,4-dihydropyridine derivatives of the present invention had bloodvessel dilating effects as potent as nifedipine.

INDUSTRIAL APPLICABILITY

The present invention provides optically active 1,4-dihydropyridinederivatives and their anion salts and method of producing them.

The optically active 1,4-dihydropyridine derivatives of the presentinvention have excellent blood vessel dilating effects and hypotensiveeffects and excellent water-solubilities so that they are useful as adrug for circulatory system such as a hypotensor or vasodilator.

What is claimed is:
 1. An optically active 1,4-dihydropyridine compoundof formula (I) ##STR30## wherein R¹ is a C₁ -C₆ alkyl; R² is aheterocycle of 5 or 6 ring atoms, the heterocycle comprising as ringatoms, in any combination, C, N, S or O and wherein the heterocycle isoptionally substituted with C₁ -C₄ alkyl, C₂ -C₅ alkoxycarbonyl,dialkylamino, carbamoyl, or cyano, provided that at least one of thering atoms is a quaternary ammonium; n is 1, 2 or 3; A is an anion. 2.The optically active 1,4-dihydropyridine compound of claim 1 wherein R²is pyridinium, pyridazinium, pyrimidinium, pyrazinium, triazinium,imidazolium, pyrazolium, oxazolium, or thiazolium.
 3. An opticallyactive 1,4-dihydropyridine compound of formula (Ia): ##STR31## whereinR¹ is C₁ -C₆ alkyl; ##STR32## is a heterocycle of 5 or 6 ring atoms, theheterocycle comprising as ring atoms, in any combination, C, N, S or O,and wherein the heterocycle is optionally substituted with C₁ -C₄ alkyl,C₂ -C₅ alkoxycarbonyl, dialkylamino, carbamoyl or cyano; n is 1, 2 or 3;A is an anion.
 4. The optically active 1,4-dihydropyridine compound ofclaim 3 wherein ##STR33## is pyridinium, pyridazinium, pyrimidinium,pyrazinium, triazinium, imidazolium, pyrazolium, oxazolium orthiazolium.
 5. An optically active 1,4-dihydropyridine compound offormula (Ib); ##STR34## wherein R¹ is C₁ -C₆ alkyl; ##STR35## is aheterocycle of 5 or 6 ring atoms, the heterocycle comprising as ringatoms, in any combination, C, N, S, or O, and wherein the heterocycle isoptionally substituted with C₁ -C₄ alkyl, C₂ -C₅ alkoxycarbonyl,dialkylamino, carbamoyl, or cyano, provided that the ring-forming atomsinclude a nitrogen atom which is not connected to the methylene group;R³ is C₁ -C₆ alkyl; n is 1, 2 or 3; A is an anion.
 6. The opticallyactive 4-dihydropyridine compound of claim 5 wherein ##STR36## ispyridinium, pyridazinium, pyrimidinium, pyrazinium, trianzinium,imidazolium, pyrazolium, oxazolium, or thiazolium.
 7. A method forpreparing an optically active 1,4-dihydropyridine compound of formula(Ia): ##STR37## wherein R¹ is C₁ -C₆ alkyl; ##STR38## is a heterocycleof 5 or 6 ring atoms, the heterocycle comprising as ring atoms, in anycombination, C, N, S, or O and wherein the heterocycle is optionallysubstituted with C₁ -C₄ alkyl, C₂ -C₅ alkoxycarbonyl, dialkylamino,carbamoyl or cyano; n is 1, 2 or 3; A is an anion, comprising the stepsof:a) reacting an optionally active 1,4-dihydropyridine compound offormula (II) ##STR39## wherein R¹ is C₁ -C₆ alkyl, with a compound offormula (III)

    X--(CH.sub.2).sub.n --X,                                   (III)

wherein X is halogen and n is 1, 2 or 3, to form a compound of formula(IV) ##STR40## b) reacting the compound produced in step a) havingformula (IV) with a heterocycle represented by formula (V) ##STR41##wherein ##STR42## comprises 5 or 6 ring atoms, the heterocyclecomprising as ring atoms, in any combination, C, N, S, or O, and whereinthe heterocycle is optionally substituted with C₁ -C₄ alkyl, C₂ -C₅alkoxycarbonyl, dialkylamino, carbamoyl, or cyano, thereby producing thecompound of formula (Ia).
 8. The method of claim 7 wherein ##STR43## ispyridinium, pyridazinium, pyrimidinium, pyrazinium, triazinium,imidazolium, pyrazolium, oxazolium or thiazolium.
 9. A method forpreparing an optically active 1,4-dihydropyridine compound of formula(Ib) ##STR44## wherein R¹ is C₁ -C₆ alkyl; ##STR45## is a heterocycle of5 or 6 ring atoms, the heterocycle comprising as ring atoms, in anycombination, C, N, S or O and wherein the heterocycle is optionallysubstituted with C₁ -C₄ alkyl, C₂ -C₅ alkoxycarbonyl, dialkylamino,carbamoyl or cyano, provided that if the heterocycle ring atom bonded tomethylene is N it does not form a quaternary ammonium; R³ is C₁ -C₆alkyl; n is 1, 2 or 3; A is an anion, comprising the steps of:a)reacting an optically active 1,4-dihydropyridine compound of formula(II) ##STR46## wherein R¹ is C₁ -C₆ alkyl, with a compound of formula(VI) ##STR47## wherein Y is halogen or hydroxyl and n is 1,2 or 3,thereby forming a compound of formula (VII) ##STR48## b) reacting thecompound of formula (VII) formed in step a) with a compound representedby X--R³, wherein R³ is C1-C6 alkyl and X is halogen, thereby formingthe compound of formula (Ib).
 10. The method of claim 9 wherein##STR49## is pyridinium, pyridazinium, pyrimidinium, pyrazinium,triazinium, imidazolium, pyrazolium, oxazolium or thiasolium.